The invention relates to delivery of drugs to the walls of body lumens and other parts of the body.
Systemic administration of drugs treats the organism as a whole, even though the disease may be localized, such as occlusion of a duct or vessel. Localization of a drug poses special problems in cases involving the walls of ducts and vessels, since, by nature, these organs serve as transport systems.
Atherosclerotic disease, for example, causes localized occlusion of the blood vessels resulting from the build-up of plaque. As the deposits increase in size, they reduce the diameter of the arteries and impede blood circulation. Angioplasty, which involves the insertion of catheters, such as balloon catheters, through the occluded region of the blood vessel in order to expand it, has been used to treat atherosclerosis.
The aftermath of angioplasty in many cases is problematic, due to restenosis, or closing of the vessel, that can occur from causes including mechanical abrasion and the proliferation of smooth muscle cells stimulated by the angioplasty treatment. Restenosis may also occur as a result of clot formation following angioplasty, due to injury to the vessel wall which triggers the natural clot-forming reactions of the blood.
In addition to the need for improved drug delivery in respect of angioplasty, and other treatments of ducts and vessels, their is need, more generally, for improved localized internal delivery of drugs in most branches of medicine for most types of drugs. In particular, there is need for improved delivery into tissue and into cells themselves within organs of the body via luminal and percutaneous access.
In one aspect, the invention features a catheter and method for delivering drug to tissue at a desired location in the body such as, the wall of a body lumen. The catheter is constructed for insertion in the body and has a catheter shaft and an expandable portion mounted on the catheter shaft. The expandable portion is expandable to a controlled pressure against the body tissue, e.g., or to fill the cross-section of the body lumen and press against the wall of the body lumen. At least a portion of the exterior surface of the expandable portion is defined by a coating of a tenaciously adhered swellable hydrogel polymer. Incorporated in the hydrogel polymer is an aqueous solution of a preselected drug to be delivered to the tissue. The hydrogel polymer and drug are selected to allow rapid release of a desired dosage of the drug from the hydrogel polymer coating during compression of the hydrogel polymer coating against the tissue or wall of the lumen when the expandable portion is expanded.
Various embodiments may include one or more of the following features. The catheter is adapted for insertion in a blood vessel, and the expandable portion is an inflatable dilatation balloon adapted for inflation at pressures in the range for effecting widening of a stenosed blood vessel. The pressure is in the range of about 1 to 20 atmospheres. The hydrogel polymer and drug are effective to release about 20% or more of the drug during inflation in the pressure range. The compression is effective to deliver the drug over a duration of about 10 minutes or less. The hydrogel polymer coating is about 10 to 50 microns thick in the swelled, uncompressed state. The hydrogel polymer is selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, and polyethylene oxides. The hydrogel polymer is polyacrylic acid. The drug is an anti-thrombogenic drug selected from the group consisting of heparin, PPACK, enoxaprin, aspirin and hirudin. The drug is an anti-proliferative drug selected from the group consisting of monoclonal antibodies, capable of blocking smooth muscle cell proliferation, heparin, angiopeptin and enoxaprin. The expandable portion is adapted for application of heat to the polymer material to control the rate of administration. The catheter further comprises a sheath member, extendable over the balloon to inhibit release of the drug into body fluids during placement of the catheter. The balloon catheter is a perfusion catheter having an expandable balloon. The expandable portion includes a stent, mountable in the blood vessel by expansion thereof. The drug is bound in the hydrogel polymer for slow time release of the drug after the compression of the hydrogel polymer by the expansion. The hydrogel polymer is a polyacrylic acid including an ammonium anion and the drug is heparin. The stent is expandable by a balloon. The stent and the balloon both include the swellable hydrogel coating incorporating the drug. The expandable portion of the catheter is prepared by introducing an aqueous solution of the drug to the hydrogel polymer coating, the catheter is introduced to the body or body lumen to position the expandable portion at the point of desired drug application, and the expandable portion is expanded to enable delivery of the drug by compression of the hydrogel polymer coating against the body tissue of the wall at the body lumen. The expandable portion is positioned at a point of occlusion in a blood vessel and the expandable portion is expanded at pressures sufficient to simultaneously dilate the vessel and deliver the drug by compression of the hydrogel polymer coating.
In a particular aspect, the invention includes a balloon catheter for delivering drug to tissue at a desired location of the wall of a blood vessel. The catheter is constructed for insertion in a blood vessel and has a catheter shaft and an expandable dilatation balloon mounted on the catheter shaft. The expandable balloon is expandable by an expansion controller to engage the tissue at a controlled pressure in the range of about 1 to 20 atmospheres to fill the cross-section of the blood vessel and press against the wall of the blood vessel. At least a portion of the exterior surface of the expandable balloon is defined by a coating of a tenaciously adhered swellable hydrogel polymer with a thickness in the range of about 10 to 50 microns in the swelled state, and incorporated within the hydrogel polymer coating is an aqueous solution of a preselected drug to be delivered to the tissue. The hydrogel polymer and drug are selected to allow rapid release of a desired dosage of about 20% or more of the drug solution from the hydrogel polymer coating during compression of the hydrogel polymer coating against body tissue or the wall of the vessel when the expandable portion is expanded in the pressure range.
In various embodiments of this aspect of the invention, the hydrogel polymer is also selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, and polyethylene oxides. The hydrogel polymer is polyacrylic acid. The drug is an anti-thrombogenic drug selected from the group consisting of heparin, PPACK, enoxaprin, aspirin and hirudin. The drug is an anti-proliferative drug selected from the group consisting of monoclonal antibodies capable of blocking smooth muscle cell proliferation, heparin, angiopeptin and enoxaprin. The catheter further comprises a sheath member, extendable over the balloon to inhibit release of the drug into body fluids during placement of the catheter.
In another aspect of the invention, the invention also features a catheter for delivering drug to tissue at a desired location of the body or wall of a body lumen. The catheter a catheter shaft and an expandable portion mounted on the catheter shaft, the expandable portion being expandable to a controlled pressure, e.g., to fill the cross-section of the body lumen and press against the wall of the body lumen. At least a portion of the exterior surface of the expandable portion is defined by a coating of a body-fluid soluble polymer, and incorporated within the soluble polymer, a preselected drug to be delivered to the tissue. The soluble polymer and drug are selected to allow release of the polymer from the surface of the balloon during compression of the polymer coating against the wall of the body lumen when the expandable portion is expanded to coat the wall of the body lumen.
Various embodiments of this aspect of the invention include the following. The polymer is selected from the group consisting of polycaprolactone, polyorthoesters, polylactic acids, polyglycolic acids, and albumin. The drug is selected from anti-thrombogenic drugs, anti-proliferative drugs and thrombolytic drugs or may be a mixture thereof. Such drugs can be delivered either simultaneously or sequentially to a desired location in the body. The drug can also be a cytotoxic drug.
In other embodiments, the drug is a naked nucleic acid or a nucleic acid incorporated into a viral vector. By naked nucleic acid is meant a uncoated single or double stranded DNA or RNA molecule not incorporated into a virus or liposome.
The expandable portion of the catheter can be adapted for application of heat to the polymer material to control the rate of administration. The polymer is a meltable polymer, and the release of the polymer is aided by the application of heat. The catheter comprises a sheath extendable over the balloon to inhibit release of drug into the body fluids during placement of said catheter. The sheath can be made of polyethylene or polyurethane. The sheath may contain a slit at the distal end to facilitate movement of the balloon in and out of the sheath. In other embodiments, the sheath may be flexible and sized to tightly surround the balloon in its deflated or slightly inflated state.
A coating such as a water soluble polymer, e.g., carbowax, gelatin, polyvinyl alcohol, polyethylene oxide or polyethylene glycol, or a biodegradable or thermally degradable polymer, e.g., albumin or pluronic gel F-127 can be used as a protective covering over the balloon to prevent release of the drug from the hydrogel until it is delivered to the desired location in the body.
In general, an advantage of the invention is the application of drugs by active diffusion directly into the tissue within the body requiring treatment penetration or impregnation of the drug into the tissue being added by the pressure applied by the balloon. The drug is preferably applied in a rapid but low-stress, low energy manner that does not further injure the tissue to be treated, and administration is selectively and evenly distributed over the treated area such that the drug can be taken up by tissue and plaque, without, e.g., being washed away by body fluids.
Further aspects of the invention, in some instances accompanied by experimental results, will now be presented. For the various experiments the same hydrogel coating as described above as being preferred, was employed, made with a coated thickness within the tolerance limits of 2 to 5 microns. In each case it was observed that the technique of the invention caused the drug or particles containing the drug to be impregnated into the tissue or thrombus well below the surface.